R-spondin1--discovery of the long-missing, mammalian female-determining gene?

Until recently, sex determination in mammals has often been described as a male determination process, with male differentiation being the active and dominant pathway, and only in its absence is the passive female pathway followed. This picture has been challenged recently with the discovery that the gene encoding R-spondin1 is mutated in human patients with female-to-male sex reversal. These findings might place R-spondin1 in the exceptional position of being the female-determining gene in mammals. In this review, possible roles of R-spondin1 during sex determination as well as questions arising from this study will be discussed.